Essential oil of Spearmint obtained from the aerial part of Mentha spicata and/or Mentha cardiaca (Lamiaceae) obtained by distillation

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.48 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12

Dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

BMCL10

Value:

52.86 mg/m³

Explanation for the modification of the dose descriptor starting point:

A 95% lower confidence limit for the benchmark dose response of 10% (BMDL10) of 60 mg/kg bw/day was calculated for relative liver weight changes induced by d-carvone. BMDL10 of 60 mg/kg bw/day for an increase in relative liver weight in the rat 90-day studies; NOAEL= 5 mg/kg bw/day and LOAEL = 30 mg/kg bw/day.

 

- ECHA Ch R.8, 2012: oral to inhalation extrapolation resulted in a factor 0.5 (default values of 50, 100 and 100% for oral, dermal and inhalation absorption respectively)

 

- ECHA Ch R.8, 2012:  Modification for exposure for workers - 8 h exposure /day = 1/sRV rat (8h)=  1/0.38 m3/kg/d

 

- ECHA Ch R.8, 2012, p 20: Respiratory volume light activity, standard conditions for worker - 8 hour (sRV human = 6,7 m3/kg/d) with relevant duration of  8 h - respiratory volume / exposure of 10 m3 (wRV).  Applicable worker = 6.7/10

60 * 0.5 * (1/0.38) * (6.7/10) = 52.86

AF for dose response relationship:

2

Justification:

ECETOC TR No. 110, 2010: LOAEL / NOAEL extrapolation, typically a value of 2 is sufficient, but if information on the dose-response curve is available a more appropriate AF should be used. Steep dose-response curve (AF =2)
Issues related to reliabilty of dose-response, LOAEL/NOAEL extrapolation and severity of effect. ECHA (2012) >= 1; 3 in marjority of cases up to 10 in exceptional cases. When the difference between the LOAEL and the NOAEL is approximately 10-fold and the effect at the LOAEL is only minor / not severe then it is not nesessary to apply a factor to take acount of this.
EFSA Journal 2014: The difference between the LOAEL ( 30 mg/kg/d) and the NOAEL ( 5 mg/kg/d) is approximately 6-fold. Histopathological changes related to treatment in the kidney which consisted of tubular necrosis, exclusively in male rats, and basophilic tubules in both sexes. From re-evaluation of the kidney slides it was concluded the renal histopathological changes observed in male rats treated with 30 or 180 mg/kg bw per day carvone min. 95 % are caused by accumulation of alpha2u -globulin in the proximal tubular cells and hence are diagnosed as alpha2u -globulin nephropathy.

AF for differences in duration of exposure:

2

Justification:

Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic data to chronic exposure (ECHA 2012, Chapter R8, p 29)

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling factor is not applied because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates [ECHA 2012, Ch R.8, p24 and p62 ]

AF for other interspecies differences:

1

Justification:

Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).[ECHA, 2012, Chapter R8, 32].

EFSA Journal 2014: Conclusions on toxicokinetics: d-Carvone toxicokinetics in humans features rapid elimination with a half life of 2.4 hours, no data are available for l-carvone. No toxicokinetic data on carvone in animals are available. The evidence from in vivo, in vitro and in silico assessments has shown that carvone metabolism is likely to be different in humans and rats – with further possible differences between metabolism in male and female rats. It is also evident that when compared with carvone itself, the metabolites are not likely to be different in terms of GI uptake or half-life in the body. Toxicokinetic data on other monoterpenes in the rat such as menthol suggest that metabolism involves conjugation to a glucuronide for which enterohepatic recirculation occurs in the rat but not in humans. Considering the molecular weight of glucuronidated carvone metabolites, they may undergo enterohepatic recirculation in rats but not in humans, making the rat more sensitive than humans for these compounds. Further investigation of toxicokinetics (including basic parameters such as absorption (bioavailability), distribution (volume of distribution), metabolism and excretion (potential enterohepatic recirculation half life, clearance) is required for both enantiomers.

AF for intraspecies differences:

3

Justification:

ECETOC TR No. 110 (2010) gives a value of 3 for the worker population.

AF for the quality of the whole database:

1

Justification:

An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity of Carvone has well been studied. However the study report itself is not available. Peer revied in EFSA report (2014), in review Report EU document on carvone (2008) and study is also referenced in the CLH report (2012). [ECHA 2012, Chapter R8, p32] Completeness and concistency of available data and reliability of alternative data (e.g. Read-across) is high. For a high confidence database, the standard default assessment factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.84 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

48

Dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A 95% lower confidence limit for the benchmark dose response of 10% (BMDL10) of 60 mg/kg bw/day was calculated for relative liver weight changes induced by d-carvone. NOAEL= 5 mg/kg bw/day  and LOAEL = 30 mg/kg bw/day

Route-to-route: Factor 1, oral to dermal extrapolation with the same units (ECHA, 2012, p67 and and p18-20); (oral absorption / absorption by dermal exposure); The data  in the Carvone CLH report 2012  provide no information on the percentage absorption after oral, dermal or inhalatory exposure, the distribution of carvone or the rate and routes of elimination from the body.  The data in the Spearmint oil DAR report (Aug 2008) provide no information on the percentage absorption after oral, dermal or inhalation exposure, the distribution of l-carvone (the main component in Spearmint Oil) or the rate and routes of elimination from the body. Therefore, default values of 50, 100 and 100% for oral, dermal and inhalation absorption respectively, will be used for the exposure and risk assessment calculations for operators, workers and by standards.    

Bioavailability differences between  human and animal species: No evidence for a difference between species for oral exposure

Bioavailability differences between test and target substances: No evidence for a difference between test and target substances.  Bioavailability data for Spearmint oils indicates similar relative bioavailability between Spearmint oils and d-Carvone

AF for dose response relationship:

2

Justification:

ECETOC TR No. 110, 2010: LOAEL / NOAEL extrapolation, typically a value of 2 is sufficient, but if information on the dose-response curve is available a more appropriate AF should be used. Steep dose-response curve (AF =2)
Issues related to reliabilty of dose-response, LOAEL/NOAEL extrapolation and severity of effect. ECHA (2012) >= 1; 3 in marjority of cases up to 10 in exceptional cases. When the difference between the LOAEL and the NOAEL is approximately 10-fold and the effect at the LOAEL is only minor / not severe then it is not nesessary to apply a factor to take acount of this.
EFSA Journal 2014: The difference between the LOAEL ( 30 mg/kg/d) and the NOAEL ( 5 mg/kg/d) is approximately 6-fold. Histopathological changes related to treatment in the kidney which consisted of tubular necrosis, exclusively in male rats, and basophilic tubules in both sexes. From re-evaluation of the kidney slides it was concluded the renal histopathological changes observed in male rats treated with 30 or 180 mg/kg bw per day carvone min. 95 % are caused by accumulation of alpha2u -globulin in the proximal tubular cells and hence are diagnosed as alpha2u -globulin nephropathy.

AF for differences in duration of exposure:

2

Justification:

Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic data to chronic exposure (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

4

Justification:

4 for allometric scaling (rats to humans) [ECHA default, 2012, Chapter R8, p 24 and p63] and [ECETOC TR No. 110, 2010].

AF for other interspecies differences:

1

Justification:

Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).[ECHA, 2012, Chapter R8, 32].

AF for intraspecies differences:

3

Justification:

ECETOC TR No. 110 (2010) A value of 3 would be inserted for the worker population.

AF for the quality of the whole database:

1

Justification:

An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity of Carvone has well been studied. However the study report itself is not available. Peer revied in EFSA report (2014), in review Report EU document on carvone (2008) and study is also referenced in the CLH report (2012). [ECHA 2012, Chapter R8, p32] Completeness and concistency of available data and reliability of alternative data (e.g. Read-across) is high. For a high confidence database, the standard default assessment factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.92 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

BMCL10

Value:

26.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

A 95% lower confidence limit for the benchmark dose response of 10% (BMDL10) of 60 mg/kg bw/day was calculated for relative liver weight changes induced by d-carvone. BMDL10 of 60 mg/kg bw/day for an increase in relative liver weight in the rat 90-day studies; NOAEL= 5 mg/kg bw/day and LOAEL = 30 mg/kg bw/day.

 

- ECHA Ch R.8, 2012: oral to inhalation extrapolation resulted in a factor 0.5 (default values of 50, 100 and 100% for oral, dermal and inhalation absorption respectively)

 

- ECHA Ch R.8, 2012:  Modification for exposure for general population = 1 /sRV rat (24h)=   1/1.15

60 * 0.5 * (1/1.15) = 26,10

AF for dose response relationship:

2

Justification:

ECETOC TR No. 110, 2010: LOAEL / NOAEL extrapolation, typically a value of 2 is sufficient, but if information on the dose-response curve is available a more appropriate AF should be used. Steep dose-response curve (AF =2)
Issues related to reliabilty of dose-response, LOAEL/NOAEL extrapolation and severity of effect. ECHA (2012) >= 1; 3 in marjority of cases up to 10 in exceptional cases. When the difference between the LOAEL and the NOAEL is approximately 10-fold and the effect at the LOAEL is only minor / not severe then it is not nesessary to apply a factor to take acount of this.
EFSA Journal 2014: The difference between the LOAEL ( 30 mg/kg/d) and the NOAEL ( 5 mg/kg/d) is approximately 6-fold. Histopathological changes related to treatment in the kidney which consisted of tubular necrosis, exclusively in male rats, and basophilic tubules in both sexes. From re-evaluation of the kidney slides it was concluded the renal histopathological changes observed in male rats treated with 30 or 180 mg/kg bw per day carvone min. 95 % are caused by accumulation of alpha2u -globulin in the proximal tubular cells and hence are diagnosed as alpha2u -globulin nephropathy.

AF for differences in duration of exposure:

2

Justification:

Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic data to chronic exposure (ECHA 2012, Chapter R8, p 29)

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling factor is not applied because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates [ECHA 2012, Ch R.8, p24 and p62 ].

AF for other interspecies differences:

1

Justification:

Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).[ECHA, 2012, Chapter R8, 32].

AF for intraspecies differences:

5

Justification:

ECETOC TR No. 110 (2010) gives a value of 5 for the general population. A value of 3 would be inserted for the worker population. The standard default for differences within a worker and general public population is applied. It is not possible to identify from the available data the potential inter-individual varaibility in susceptibility to substance induced toxicity.

AF for the quality of the whole database:

1

Justification:

An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity of Carvone has well been studied. However the study report itself is not available. Peer revied in EFSA report (2014), in review Report EU document on carvone (2008) and study is also referenced in the CLH report (2012). [ECHA 2012, Chapter R8, p32] Completeness and concistency of available data and reliability of alternative data (e.g. Read-across) is high. For a high confidence database, the standard default assessment factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

No adverse effects have been observed at the limit dose in the reported studies.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A 95% lower confidence limit for the benchmark dose response of 10% (BMDL10) of 60 mg/kg bw/day was calculated for relative liver weight changes induced by d-carvone. NOAEL= 5 mg/kg bw/day  and LOAEL = 30 mg/kg bw/day

Route-to-route:Factor 1, oral to dermal extrapolation with the same units (ECHA, 2012, p67 and and p18-20); (oral absorption / absorption by dermal exposure); The data  in the Carvone CLH report 2012  provide no information on the percentage absorption after oral, dermal or inhalatory exposure, the distribution of carvone or the rate and routes of elimination from the body.  The data in the Spearmint oil DAR report (Aug 2008) provide no information on the percentage absorption after oral, dermal or inhalation exposure, the distribution of l-carvone (the main component in Spearmint Oil) or the rate and routes of elimination from the body. Therefore, default values of 50, 100 and 100% for oral, dermal and inhalation absorption respectively, will be used for the exposure and risk assessment calculations for operators, workers and by standards.    

Bioavailability differences between  human and animal species:No evidence for a difference between species for oral exposure

Bioavailability differences between test and target substances:No evidence for a difference between test and target substances.  Bioavailability data for Spearmint oils indicates similar relative bioavailability between Spearmint oils and d-Carvone

AF for dose response relationship:

2

Justification:

ECETOC TR No. 110, 2010: LOAEL / NOAEL extrapolation, typically a value of 2 is sufficient, but if information on the dose-response curve is available a more appropriate AF should be used. steep dose-response curve (AF =2)
AF = 2. Issues related to reliabilty of dose-response, LOAEL/NOAEL extrapolation and severity of effect. ECHA (2012) >= 1; 3 in marjority of cases up to 10 in exceptional cases. When the difference between the LOAEL and the NOAEL is approximately 10-fold and the effect at the LOAEL is only minor / not severe then it is not nesessary to apply a factor to take acount of this. EFSA Journal 2014: The difference between the LOAEL ( 30 mg/kg/d) and the NOAEL ( 5 mg/kg/d) is approximately 6-fold. Histopathological changes related to treatment in the kidney which consisted of tubular necrosis, exclusively in male rats, and basophilic tubules in both sexes. From re-evaluation of the kidney slides it was concluded the renal histopathological changes observed in male rats treated with 30 or 180 mg/kg bw per day carvone min. 95 % are caused by accumulation of alpha2u -globulin in the proximal tubular cells and hence are diagnosed as alpha2u -globulin nephropathy.

AF for differences in duration of exposure:

2

Justification:

Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic data to chronic exposure (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

4

Justification:

4 for allometric scaling (rats to humans) [ECHA default, 2012, Chapter R8, p 24 and p63] and [ECETOC TR No. 110, 2010].

AF for other interspecies differences:

1

Justification:

Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).[ECHA, 2012, Chapter R8, 32].

AF for intraspecies differences:

5

Justification:

ECETOC TR No. 110 (2010) gives a value of 5 for the general population.

AF for the quality of the whole database:

1

Justification:

An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity of Carvone has well been studied. However the study report itself is not available. Peer revied in EFSA report (2014), in review Report EU document on carvone (2008) and study is also referenced in the CLH report (2012). [ECHA 2012, Chapter R8, p32] Completeness and concistency of available data and reliability of alternative data (e.g. Read-across) is high. For a high confidence database, the standard default assessment factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route: Factor 1 Oral to oral extrapolation with the same units (ECHA, 2012, p67 and p18-20 ); (oral absorption /absorption by ingestion); The data  in the Carvone CLH report 2012  provide no information on the percentage absorption after oral, dermal or inhalatory exposure, the distribution of carvone or the rate and routes of elimination from the body.  The data in the Spearmint oil DAR report (Aug 2008) provide no information on the percentage absorption after oral, dermal or inhalation exposure, the distribution of l-carvone (the main component in Spearmint Oil) or the rate and routes of elimination from the body. Therefore, default values of 50, 100 and 100% for oral, dermal and inhalation absorption respectively, will be used for the exposure and risk assessment calculations for operators, workers and by standards.    

Bioavailability differences between  human and animal species: No evidence for a difference between species for oral exposure

Bioavailability differences between test and target substances: No evidence for a difference between test and target substances.  Bioavailability data for Spearmint oils indicates similar relative bioavailability between Spearmint oils and d-Carvone

AF for dose response relationship:

2

Justification:

ECETOC TR No. 110, 2010: LOAEL / NOAEL extrapolation, typically a value of 2 is sufficient, but if information on the dose-response curve is available a more appropriate AF should be used. Steep dose-response curve (AF =2)
Issues related to reliabilty of dose-response, LOAEL/NOAEL extrapolation and severity of effect. ECHA (2012) >= 1; 3 in marjority of cases up to 10 in exceptional cases. When the difference between the LOAEL and the NOAEL is approximately 10-fold and the effect at the LOAEL is only minor / not severe then it is not nesessary to apply a factor to take acount of this.
EFSA Journal 2014: The difference between the LOAEL ( 30 mg/kg/d) and the NOAEL ( 5 mg/kg/d) is approximately 6-fold. Histopathological changes related to treatment in the kidney which consisted of tubular necrosis, exclusively in male rats, and basophilic tubules in both sexes. From re-evaluation of the kidney slides it was concluded the renal histopathological changes observed in male rats treated with 30 or 180 mg/kg bw per day carvone min. 95 % are caused by accumulation of alpha2u -globulin in the proximal tubular cells and hence are diagnosed as alpha2u -globulin nephropathy.

AF for differences in duration of exposure:

2

Justification:

Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic data to chronic exposure (ECHA 2012, Chapter R8, p 29)

AF for interspecies differences (allometric scaling):

4

Justification:

4 for allometric scaling (rats to humans) [ECHA default, 2012, Chapter R8, p 24 and p60] and [ECETOC TR No. 110, 2010].

AF for other interspecies differences:

1

Justification:

Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).[ECHA, 2012, Chapter R8, 32].

AF for intraspecies differences:

5

Justification:

ECETOC TR No. 110 (2010) gives a value of 5 for the general population. A value of 3 would be inserted for the worker population.

AF for the quality of the whole database:

1

Justification:

An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity of Carvone has well been studied. Study report itself is not available. Peer revied in EFSA report (2014), in review Report EU document on carvone (2008) and study is also referenced in the CLH report (2012). [ECHA 2012, Chapter R8, p32] Completeness and concistency of available data and reliability of alternative data (e.g. Read-across) is high. For a high confidence database, the standard default assessment factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified